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PSP/CBS Therapeutic Target Index
PSP/CBS Therapeutic Target Index
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">PSP/CBS Therapeutic Target Index</th>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">MAPT (tau) mRNA</td>
<td>Antisense oligonucleotide (ASO)</td>
</tr>
<tr>
<td class="label">MAPT splicing</td>
<td>Splice-modulating ASO</td>
</tr>
<tr>
<td class="label">MAPT transcription</td>
<td>Gene therapy</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Tau oligomerization</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">Tau filament assembly</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody (mid-region)</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody (N-terminal)</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody</td>
</tr>
<tr>
<td class="label">Phospho-tau (pSer396/404)</td>
<td>Active vaccine</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">O-GlcNAcylation</td>
<td>O-GlcNAcase (OGA) inhibitor</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Kinase inhibitors</td>
</tr>
<tr>
<td class="label">Acetylation</td>
<td>Acetyltransferase inhibitors</td>
</tr>
PSP/CBS Therapeutic Target Index
<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">PSP/CBS Therapeutic Target Index</th>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">MAPT (tau) mRNA</td>
<td>Antisense oligonucleotide (ASO)</td>
</tr>
<tr>
<td class="label">MAPT splicing</td>
<td>Splice-modulating ASO</td>
</tr>
<tr>
<td class="label">MAPT transcription</td>
<td>Gene therapy</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Tau oligomerization</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">Tau filament assembly</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody (mid-region)</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody (N-terminal)</td>
</tr>
<tr>
<td class="label">Extracellular tau</td>
<td>Passive antibody</td>
</tr>
<tr>
<td class="label">Phospho-tau (pSer396/404)</td>
<td>Active vaccine</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">O-GlcNAcylation</td>
<td>O-GlcNAcase (OGA) inhibitor</td>
</tr>
<tr>
<td class="label">Phosphorylation</td>
<td>Kinase inhibitors</td>
</tr>
<tr>
<td class="label">Acetylation</td>
<td>Acetyltransferase inhibitors</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Mitochondrial function</td>
<td>Coenzyme Q10</td>
</tr>
<tr>
<td class="label">Mitochondrial biogenesis</td>
<td>PGC-1α activator</td>
</tr>
<tr>
<td class="label">Complex I support</td>
<td>Small molecule</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Microglia activation</td>
<td>CSF1R antagonist</td>
</tr>
<tr>
<td class="label">Complement activation</td>
<td>C1q inhibitor</td>
</tr>
<tr>
<td class="label">TREM2 signaling</td>
<td>TREM2 agonist</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">BDNF signaling</td>
<td>TrkB agonist</td>
</tr>
<tr>
<td class="label">GDNF delivery</td>
<td>Gene therapy</td>
</tr>
<tr>
<td class="label">CNTF signaling</td>
<td>Protein delivery</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Synaptic plasticity</td>
<td>PDE inhibitors</td>
</tr>
<tr>
<td class="label">Excitotoxicity</td>
<td>NMDA modulation</td>
</tr>
<tr>
<td class="label">Synuclein interaction</td>
<td>Alpha-synuclein modulation</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Dopamine replacement</td>
<td>Levodopa/carbidopa</td>
</tr>
<tr>
<td class="label">Dopamine agonist</td>
<td>Pramipexole, rotigotine</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Pseudobulbar affect</td>
<td>Dextromethorphan/quinidine</td>
</tr>
<tr>
<td class="label">Depression</td>
<td>SSRIs</td>
</tr>
<tr>
<td class="label">Sleep disorder</td>
<td>Melatonin, modafinil</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">L-type calcium channel</td>
<td>Dihydropyridine antagonists</td>
</tr>
<tr>
<td class="label">Ryanodine receptor</td>
<td>Dantrolene</td>
</tr>
<tr>
<td class="label">Mitochondrial calcium</td>
<td>MCU inhibitors</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Autophagy induction</td>
<td>mTOR inhibition</td>
</tr>
<tr>
<td class="label">Autophagy induction</td>
<td>TFEB activation</td>
</tr>
<tr>
<td class="label">Proteasome enhancement</td>
<td>USP30 inhibitors</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Modality</td>
</tr>
<tr>
<td class="label">Ketone metabolism</td>
<td>Ketogenic diet</td>
</tr>
<tr>
<td class="label">Glycolysis modulation</td>
<td>HK2 inhibitors</td>
</tr>
<tr>
<td class="label">Astrocyte metabolism</td>
<td>Lactate transporters</td>
</tr>
<tr>
<td class="label">Category</td>
<td>Trial Count</td>
</tr>
<tr>
<td class="label">Tau immunotherapy</td>
<td>8+</td>
</tr>
<tr>
<td class="label">Tau-lowering ASO</td>
<td>3+</td>
</tr>
<tr>
<td class="label">OGA inhibition</td>
<td>2+</td>
</tr>
<tr>
<td class="label">Neuroprotection</td>
<td>5+</td>
</tr>
<tr>
<td class="label">symptomatic/supportive</td>
<td>15+</td>
</tr>
<tr>
<td class="label">Priority Rank</td>
<td>Target Category</td>
</tr>
<tr>
<td class="label">1</td>
<td>Tau production (MAPT)</td>
</tr>
<tr>
<td class="label">2</td>
<td>Tau aggregation</td>
</tr>
<tr>
<td class="label">3</td>
<td>Tau immunotherapy</td>
</tr>
<tr>
<td class="label">4</td>
<td>O-GlcNAcase</td>
</tr>
<tr>
<td class="label">5</td>
<td>Neuroinflammation</td>
</tr>
<tr>
<td class="label">6</td>
<td>Autophagy enhancement</td>
</tr>
<tr>
<td class="label">7</td>
<td>Mitochondrial function</td>
</tr>
<tr>
<td class="label">8</td>
<td>Neurotrophic support</td>
</tr>
</table>
Overview
This index provides a comprehensive mapping of therapeutic targets for 4R-tauopathies, specifically [progressive supranuclear palsy](/diseases/steele-richardson-olszewski-syndrome) (PSP) and [corticobasal syndrome](/diseases/corticobasal-degeneration) (CBS/CBD). The page integrates the therapeutic pipeline, clinical trial status, and mechanism-to-treatment gaps to identify priority areas for research and development.
PSP and CBS represent the two major clinical syndromes within the 4R-tauopathy spectrum, sharing neuropathological features but differing in regional distribution and clinical presentation[@hoglinger2017][@armstrong2013]. This index organizes therapeutic approaches by molecular target and maps them to the disease mechanisms they aim to address.
Target Taxonomy
Category 1: Tau-Directed Therapies
1.1 Tau Production Lowering
Mechanism-to-Treatment Gap: ASO approaches have demonstrated the strongest pharmacodynamic signal in humans with dose-dependent CSF tau reduction[@mummery2023]. However, delivery requires intrathecal administration, limiting practical accessibility. Next-generation oral or systemic delivery systems are needed.
1.2 Tau Aggregation Inhibition
Mechanism-to-Treatment Gap: Aggregation inhibitors address the seed propagation mechanism critical to tau spreading. However, optimal blood-brain barrier penetration and adequate brain concentrations remain challenging. Early intervention may be required for efficacy.
1.3 Tau Immunotherapy
Mechanism-to-Treatment Gap: Anti-tau antibodies have failed in PSP specifically, raising questions about epitope selection, target engagement timing, and whether extracellular neutralization addresses the core intracellular pathology. Next-generation approaches need 4R-tau-specific epitope targeting and better CNS penetration.
1.4 Tau Post-Translational Modification
Mechanism-to-Treatment Gap: OGA inhibitors aim to shift tau toward less pathological conformations by increasing O-GlcNAcylation. Early biomarker data suggest target engagement, but clinical efficacy remains to be demonstrated. The approach is attractive for chronic oral dosing.
Category 2: Neuroprotective and Disease-Modifying Approaches
2.1 Mitochondrial Protection
Mechanism-to-Treatment Gap: Mitochondrial dysfunction is prominent in PSP pathology, but CoQ10 trials failed to show efficacy. This suggests either timing (too late in disease course) or target inadequacy (CoQ10 may not address the primary mitochondrial deficit).
2.2 Neuroinflammation Modulation
Mechanism-to-Treatment Gap: Neuroinflammation is a prominent feature of PSP/CBS, but anti-inflammatory approaches have not been systematically tested in human trials. Timing and which inflammatory pathway to target remain unclear.
2.3 Neurotrophic Factor Support
Mechanism-to-Treatment Gap: Neurotrophic approaches face delivery challenges across the blood-brain barrier and ensuring proper distribution to affected brain regions. Gene therapy approaches are advancing but require surgical delivery.
2.4 Synaptic Protection
Mechanism-to-Treatment Gap: Synaptic loss correlates with cognitive decline, but no synaptic protective therapies have reached clinical testing in PSP/CBS. Biomarkers for synaptic integrity are needed.
Category 3: Symptomatic Treatments
3.1 Dopaminergic Therapy
Mechanism-to-Treatment Gap: Levodopa provides modest and often transient benefit in PSP, less than in Parkinson's disease, reflecting significant non-dopaminergic pathology. No optimized PSP-specific dopaminergic regimens exist.
3.2 Non-Motor Symptom Management
Mechanism-to-Treatment Gap: Non-motor symptoms significantly impact quality of life but are addressed with repurposed medications not optimized for PSP/CBS-specific pathophysiology.
Category 4: Emerging and Investigational Approaches
4.1 Calcium Homeostasis
Mechanism-to-Treatment Gap: Calcium dysregulation is prominent in PSP neurons but no clinical candidates have advanced beyond preclinical testing.
4.2 Protein Clearance Enhancement
Mechanism-to-Treatment Gap: Enhancing tau clearance through autophagy is conceptually attractive but pharmacologic induction faces toxicity concerns and incomplete understanding of which clearance pathway to engage.
4.3 Cellular Energy Metabolism
Mechanism-to-Treatment Gap: Metabolic deficits in PSP neurons are well-documented but metabolic therapies remain at early experimental stages.
Clinical Trial Landscape Summary
Active/Pending Trials by Mechanism
Trial Design Considerations for PSP/CBS
Mechanism-to-Treatment Gap Analysis
Critical Gaps
Strategic Priorities
Therapeutic Target Summary Matrix
References
See Also
- [Tau-Targeting Therapeutics Pipeline](/therapeutics/tau-therapeutics-pipeline)
- [Progressive Supranuclear Palsy](/diseases/steele-richardson-olszewski-syndrome)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
- [4R Tauopathy Mechanisms](/mechanisms/4r-tauopathy-mechanisms)
- [Tau Immunotherapy](/therapeutics/tau-immunotherapy)
- [Tau Aggregation Inhibitors](/therapeutics/tau-aggregation-inhibitors)
- [PSP Clinical Trial Platform](/clinical-trials/psp-clinical-trial-platform)
- [AMX0035 PSP Trial](/clinical-trials/amx0035-psp)
- [CurePSP Research](https://www.psp.org/iwanttolearn/research/)
Related Hypotheses
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
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- [Metabolic Reprogramming via Microglial Glycolysis Inhibition](/hypothesis/h-38292315) — <span style="color:#ffd54f;font-weight:600">0.49</span> · Target: HK2
- [Mitochondrial Calcium Buffering Enhancement via MCU Modulation](/hypothesis/h-aa8b4952) — <span style="color:#ffd54f;font-weight:600">0.49</span> · Target: MCU
- [TREM2 Conformational Stabilizers for Synaptic Discrimination](/hypothesis/h-044ee057) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: TREM2
- [TREM2-mediated microglial tau clearance enhancement](/hypothesis/h-b234254c) — <span style="color:#ffd54f;font-weight:600">0.55</span> · Target: TREM2
- [Designer TRAK1-KIF5 fusion proteins accelerate therapeutic mitochondrial delivery](/hypothesis/h-346639e8) — <span style="color:#ffd54f;font-weight:600">0.48</span> · Target: TRAK1_KIF5A
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